Methods and apparatuses for manufacturing a plurality of cartridges of medical buffering solution with a common ph

ABSTRACT

The pH of a buffer or other medical solution in a plurality of containers can be adjusted and maintained by partially filling each container with a sodium bicarbonate solution so that a headspace remains over the solution. The headspace is filled with gas having a known CO 2  concentration, and a fixed and precise pH will result after the CO 2  is dissolved and the solution fully equilibrates.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application claims the benefit of prior provisionalapplication No. 61/517,811 (Attorney Docket No. 36312-711.101), filed onApr. 26, 2011, the entire contents of which is incorporated herein byreference.

BACKGROUND OF THE INVENTION

A buffer solution is a solution that, when mixed with another solution,tends to bring the pH of other solution toward the pH of the buffer.Medical buffer solutions are frequently used in antidotes, dialysates,body replacement fluids, body irrigating solutions, and cardiacperfusates. One of the most commonly used medical bicarbonate buffersolutions consists of sodium bicarbonate (NaHCO₃) mixed with water,often called “sodium bicarbonate solution.” A common use for sodiumbicarbonate solution is to raise the pH of local anesthetics towardphysiologic pH in order to hasten the onset of analgesia and reduceinjection pain.

Sodium bicarbonate solutions are often more or less effective formedical purposes depending on their pH. Accordingly, if a sodiumbicarbonate solution is intended for a particular use, if would be bestto manufacture and maintained the solution at the optimum pH for suchuse.

Commercially produced medical sodium bicarbonate solutions fall farshort of this objective. For example, commercially available bufferingsolutions set the pH range from pH 7.0 to pH 8.5. An assay of a sampleof commercially available sodium bicarbonate solutions conducted by theinventors herein showed a pH range from 7.62 to 8.26; presumably theactual range of the product available in the marketplace is even widerthan the range shown in this sample assay.

It must be appreciated in this context that a medical buffer having anactual pH of 7.0 may perform significantly differently than a medicalbuffer having an actual pH of 8.5. This is true whether the medicalbuffer is designed to buffer the pH of the body's fluids, for instancein the treatment of acidosis, or the medical buffer is designed tobuffer the pH of a parenteral solution prior to its use, for instance tobuffer a local anesthetic injection. In the latter example, the ratio ofbuffer solution to anesthetic solution would necessarily varysignificantly if the pH of the bicarbonate solution were 7.0 compared to8.5. Prior art methods of combining buffering solution with parenteralsolutions do not use buffering solution having a precisely known pH inorder to consistently add the same ratio of buffering solution to theparenteral solution, nor do they include manufacturing and storagemethods and apparatuses designed to establish and maintain the pH of thebuffering solution in an optimal range.

U.S. Patent Publication 2011/0005958, commonly owned and invented withthe present application, describes a method and system for adjusting thepH of a sodium bicarbonate buffer solutions in small cartridges orcontainers. The cartridges are completely filled with a buffer solution,and the containers are maintained in a controlled environment of anequilibration chamber with a high carbon dioxide content. The containersare maintained for an extended period of time, typically hours orlonger, in order for full equilibration to occur and for the pH tostabilize. While very effective, these methods often require a lengthyperiod for full equilibration which increases the cost of the process.Moreover, the degree to which the pH can be lowered is limited by thepressure in the equilibration chamber which is usually kept at or nearambient pressure.

For these reasons, it would be desirable to provide improved andalternative methods for producing a plurality of containers of bufferingsolutions having the same precisely controlled pH, where the pH in eachcontainer package is substantially identical and consistent, and so thatmedical practitioners can utilize buffers that are more specificallytailored for their medical uses than the buffers available at present.It would be further desirable to provide methods and systems forproducing packaged buffer solutions which allow for the preparation ofunlimited numbers of packages, such as cartridges, capsules, carpules,vials, and other containers, each of which contains a stable andprecisely known pH. Such methods will preferably be capable of beingperformed rapidly with minimum processing time necessary to allow forCO₂ absorption into the buffer, and will further preferably allow for ahigher pressure equilibration to lower the final pH of the solution. Atleast some of these objectives will be met by the inventions describedbelow. Such methods and systems should provide for the economicalpreparation of such buffer solution containers, should allow thecontainers to be for long periods of time while maintaining pHstability, and should be compatible with sterilization protocols andsystems. At least some of these objectives will be met by the inventionsdescribed below.

Description of the Background Art. U.S. Patent Publication 2011/0005958has been described above. Glass vials and cartridges for storing medicalsolutions are described in U.S. Pat. Nos. 1,757,809; 2,484,657;4,259,956; 5,062,832; 5,137,528; 5,149,320; 5,226,901; 5,330,426; and6,022,337. Exemplary disposable drug cartridge that could be loaded withbuffer solution in accordance with the present invention are describedin U.S. Pat. No. 5,603,695 and in commonly owned, co-pending applicationUS2009/0292271 (U.S. Ser. No. 12/406,670), both of which areincorporated herein by reference. Devices for maintaining a dissolvedgas in solution in a pouch are described in U.S. Pat. Nos. 5,690,215;5,610,170; and 4,513,015, and U.S. Patent Publ. No. 2007/0265593. Otherpatents and applications of interest include U.S. Pat. Nos. 2,604,095;3,993,791; 4,154,820; 4,630,727; 4,654,204; 4,756,838; 4,959,175;5,296,242; 5,383,324; 5,603,695; 5,609,838; 5,779,357; and U.S. PatentPubl. No. 2004/0175437.

BRIEF SUMMARY OF THE INVENTION

The present invention provides for the manufacture of a plurality ofbuffering or other medical solution containers where the solution withineach container will have a precise and uniform pH. The pH of a sodiumbicarbonate buffer or other solution depends upon the partial pressureof CO₂ in the solution. In accordance with the present invention, aplurality of containers are partially filled with a predetermined volumeof solution selected to leave a specific preselected headspace volume ofabove the buffer. The headspace is filled with a gas rich in CO₂, andthe container is then sealed. The amount of CO₂ in the headspace isselected so that the pH of the solution is fixed at a target value afterthe CO₂ has dissolved into the aqueous solution. By maintaining theaqueous solution and the gas within headspace under a known temperature,e.g. room temperature or 20° C., and pressure (usually elevated aboveambient pressure) after the container is sealed, the partial pressure ofthe CO₂ in the headspace and the solution within the container willequilibrate. The method allows the manufacturer to control the pH of thesolution in the container by adjusting any one or more of thetemperature, the pressure under which the contents of the containers areheld, and the volume and concentration of CO₂ gas that is placed in theheadspace during manufacture.

Methods of the present invention are particularly advantageous in thatthey simplify the pH adjustment process, shorten the time required forthe containers to be maintained in a processing environment, and allowfor large volumes of CO₂ to be dissolved in the solution to lower the pHof the solution after equilibration. In particular, when compared to theprocess described in U.S. Patent Publication 2011/0005958, the processof the present invention is simplified since the containers do not needto be completely filled. Moreover, the time required to maintain thecontainers in a processing environment can be shortened since, after thecontainers are sealed, they may be removed from the processingenvironment and simply stored until being shipped for use. Additionally,lower pH's may be achieved without having to maintain higher pressuresthroughout a large equilibration chamber.

In specific aspects of the present invention, a method for adjusting thepH of a medical or other solution in the container comprises filling thecontainer with a preselected volume of bicarbonate solution. The volumeof the bicarbonate solution is selected to leave a predetermined volumeof headspace over the buffer in the container. The headspace is thespace or open volume below an open top of the container and above thesurface of the solution in the container when the container is heldvertically. The volume of the headspace is equal to the interior volumeof the container less the preselected volume of the bicarbonate solutionwhich is added to the container.

After the container is filled with the preselected volume of thebicarbonate solution, the headspace will be filled with a carbon dioxide(CO₂)-rich gas. The container is then sealed, and the CO₂-rich gasdissolves into the buffer solution to lower the pH of the buffer to adesired value, typically in the range from 7.4 to 8, preferably in therange from 7.6 to 7.8. The volume of bicarbonate buffer is typically inthe range from 1.6 ml to 2.1 ml, typically in the range from 1.8 ml to1.9 ml, and the headspace volume is typically in the range from 0.16 mlto 2.1 ml, usually from 0.18 ml to 0.19 ml. The CO₂-rich gas willtypically have a CO₂ concentration of at least 75% by volume, usuallybeing at least 98% by volume, and frequently being essentially pure CO₂gas.

The pH of the buffer or other medical solutions which is achieved willdepend on a number of factors, including the volume of the CO₂-rich gas,the concentration of CO₂ in the CO₂-rich gas, the temperature, and thepressure under which the gas is maintained within the container. Whilethe CO₂-gas may be maintained at ambient pressure, often it will bemaintained at a pressure above ambient. For example, the container mayhave a movable plug or other barrier with a force being applied againstthe plug or barrier in order to raise the pressure on the solution andCO₂-gas inside the container. For example, the force may be applied by aspring element, a screw element, or the like.

One advantage of the present invention is that by dissolving CO₂ fromthe headspace into the solution, the amount of CO₂ in the buffer may behigher than can be achieved by the ambient pressure equilibrationprovided by a U.S. Patent Publication 2011/0005958. In some instances,however, it may be desirable to initially treat the containers withbuffers and other solutions using the methods described in U.S. PatentPublication 2011/0005958, followed by the methods of the presentinvention. For example, the cartridges may be partially filled with thebicarbonate buffer as described herein, and then placed in a controlledequilibration environment filled with a CO₂-rich gas prior to sealingthe openings. The controlled equilibration environment is typically alarge enclosure holding many open cartridges and having elevated CO₂levels, as taught in U.S. Patent Publication 2011/0005958. After theopen cartridges are left within the controlled equilibration environmentfor a preselected duration so that the pH is initially stabilized at atarget value, the containers may be sealed and pressure applied to thebuffer within the containers, typically using a spring element andmovable plug as described in detail hereinafter, so that additional CO₂is dissolved within the buffer to further lower the pH beyond thatachieved by the initial equilibration. In such methods, the filling stepof the present invention is achieved during the initialpre-equilibration, which occurs in the controlled equilibrationenvironment which is filled with the CO₂-rich gas.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a cartridge useful in the practice of the presentinvention.

FIG. 2 illustrates another embodiment of a cartridge useful in thepractice of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

A first embodiment of this invention is shown in FIG. 1. A container 10comprises a glass cartridge with a pierceable septum 12 at one end and aslideable plunger 13 at the other end. The interior of the container 10has been filled to 85% of its volumetric capacity with sodiumbicarbonate solution 14 having a concentration of 8.4% CO₂ by weight.The remaining 15% of the cartridge volume is filled with CO₂ gas 15 at aconcentration of 98%-100% by volume. The gas and liquid contents of thecontainer 10 are maintained under pressure by the slideable plunger 13,which applies ambient pressure (typically 1 atm.) to the contents of thecartridge. Over the course of 48 hours, the partial pressure of the CO₂gas in the headspace 15 will equilibrate with the partial pressure ofthe CO₂ in the sodium bicarbonate solution 14, and the pH of a pluralityof cartridges manufactured using this method will be approximately 7.50.

In another embodiment shown in FIG. 2, container 10′ comprises a spring18 or similar mechanism which presses against the plunger 13 in order tocreate an above-atmospheric pressure inside container 10′. The higherpressure is exerted against both the gas in the headspace 15 and theliquid sodium bicarbonate buffer 14. If the other variables set forth inthe first embodiment (above) are the same, then the pH of the pluralityof cartridges manufactured using this method would equilibrate to acommon, more acidic, pH. The specific pH would depend on the amount ofspring force selected and implemented using this method. The upper limit(corresponding to lowest pH) occurs when the pressure is sufficient todrive all of the CO₂ gas into solution at the storage temperature. Thatis, at some point, all of the CO₂ gas initially present in the headspace15 would be driven into solution, leaving no headspace 15 with plunger13 moved fully to the right so that solution 14 would entirely fill theinterior of cartridge 10′, including all the volume between plunger 13and cap 12. In that state, the pH of the solution could go no lowerregardless of the amount of force exerted by spring 18.

In still another embodiment not shown in a figure, the CO₂ concentrationof gas initially in the headspace may be less than the 98%-100% setforth in the earlier example with all the other variables may remain thesame. In such an embodiment, the partial pressure of CO₂ in solutionafter equilibration would be lower, and the pH of the fully equilibratedbicarbonate buffer solution would be higher (more basic) than in thefirst example. The actual post-equilibration pH would be determined bythe concentration of the CO₂ gas in the headspace.

Other embodiments of the invention may include different combinations ofspring force, temperature, and concentrations of CO₂ gas which can beselected to achieve different targeted pH levels.

The present invention would also include containers having othermechanisms for applying pressure to the contents of the container, suchas gas springs, screw mechanism, and the like.

The foregoing methods and apparatuses may be used to create containershaving a common pH for any medical solution having the characteristicthat the pH of the solution changes based on the partial pressure of CO₂in solution, where CO₂ can enter or leave solution. Accordingly, amongother solutions and medical uses, the foregoing method and apparatusescould be used to create medical bicarbonate solutions that would have aconsistent pH, which would optimize their use in treating, among otherthings, metabolic acidosis.

While the above is a description of preferred embodiments of theinvention, various alternatives, modifications, and equivalents may beused. Therefore, the above description should not be taken as limitingthe scope of the invention which is disclosed.

While the above is a complete description of the preferred embodimentsof the invention, various alternatives, modifications, and equivalentsmay be used. Therefore, the above description should not be taken aslimiting the scope of the invention which is defined by the appendedclaims.

1. A method for adjusting the pH of a medical solution in a container,said method comprising: filling the container with a preselected volumeof a bicarbonate solution to leave a predetermined volume of headspaceover the buffer; filling the headspace with a CO₂-rich gas; sealing thecontainer to allow the CO₂-rich gas to dissolve in the buffer to adjusta pH of the buffer to a desired value.
 2. A method as in claim 1,wherein the volume of bicarbonate buffer is in the range from 1.6 ml to2.1 ml and the headspace volume is in the range from 0.16 ml to 0.21 ml.3. A method as in claim 1, wherein the CO₂-rich gas has a CO₂concentration of at least 75%.
 4. A method as in claim 3, wherein theCO₂ concentration is at least 98%.
 5. A method as in claim 1, whereinthe contents of the container are maintained at ambient pressure aftersealing.
 6. A method as in claim 5, wherein the cartridge has a moveableplug.
 7. A method as in claim 1, wherein the contents of the containerare maintained at a pressure above ambient after sealing.
 8. A method asin claim 7, wherein the container has a moveable plug and the pressureis maintained by applying a spring-force to the plug.
 9. A method as inclaim 1, further comprising holding the containers in a controlledatmosphere after filling, but before sealing so that the bufferpre-equilibrates with the atmosphere.
 10. A method as in claim 9,wherein the controlled atmosphere comprises the CO₂-rich gas, whereinthe headspace fills with the CO₂-rich gas while the bufferpre-equilibrates.